Experimental models of cognitive deficits in schizophrenia have supported a role for nicotinic cholinergic dysfunction, and the pharmacologic modulation of the nicotinic receptor has been a recent target of new treatment interventions. Recent work has provided important experimental leverage to investigate cholinergic mechanisms of attention networks. Sustained attention recruits a network of brain regions, most prominently frontal-parietal networks, particularly in the right hemisphere. A task developed with a rodent model, the sustained attention task (SAT), which includes a distractor condition (dSAT), has been developed and applied in schizophrenia patients. Preliminary work demonstrates that the patients show poor performance overall, particularly during the dSAT condition. In healthy subjects, the dSAT condition recruits brain activity in the right dorsolateral prefrontal cortex, which has been shown to be hypoactive in schizophrenia patients. We propose to use functional magnetic resonance imaging (fMRI) to measure cerebral perfusion with arterial spin labeling (ASL), an indirect measurement of neuronal activity, in two separate sessions (within subjects) with nicotine and without nicotine. ASL provides a quantifiable measure of cerebral perfusion, unlike the blood oxygenation-level dependent (BOLD) measure, and it can capture differences in baseline perfusion introduced by differences in control and study groups or a pharmacologic agent such as nicotine. ASL is also better- suited to data collection over long blocks necessary to study sustained attention. Specifically, we propose the following: Specific Aim 1 - Neural effects of nicotine during SAT performance: To compare ASL activation with or without prior administration of nicotine in the attention-related neurocircuits in schizophrenic and healthy tobacco smokers using a sustained attention task (SAT) to activate frontal-parietal cortex. Hypothesis 1. Relative to sessions without, nicotine administration will increase cerebral activation in frontal- parietal cortex during a sustained attention task (SAT) in both schizophrenic and control smokers, following nicotine, compared to task activation without preceding nicotine. Specific Aim 2 - Differential neural effects of nicotine during dSAT performance: To compare ASL activation during distraction in the sustained attention task (dSAT) in healthy tobacco smokers with our schizophrenic subjects, at baseline (without nicotine) and after smoking. Hypothesis 2a. Without nicotine, schizophrenic subjects will exhibit less activation than normal control smokers in attention-related region neurocircuits during the dSAT. Hypothesis 2b. With nicotine, the increase in dSAT-related activation of neurocircuits will be greater in schizophrenic subjects than in normal control smokers. PUBLIC HEALTH RELEVANCE: This research project is important because it will use brain imaging to yield information about the bases of differences in brain networks involved in maintaining and focusing attention between schizophrenics and the normal population. Dysfunction of these attention networks may be responsible for a significant proportion of the impairment of functioning commonly seen in those suffering from schizophrenia. Tobacco smoking may improve the functioning of attention networks, but the current medications used to treat schizophrenia do not significantly improve attention. The proposed research would help provide a biomarker for procognitive effects caused by tobacco that then can be applied to an animal model for prescreening of possible non-tobacco procognitive drug candidates in individuals suffering from schizophrenia.